Changes in the Immune Response of RA Patients Induced By 1 Year of Tocilizumab

Cesar Diaz-Torné¹, Paula Estrada², Patricia Moya³, Maria A. Ortiz⁴, Diana de la Fuente⁵, Mireia Moreno⁶, Noemí Busquets⁷, Julio Ramírez⁸, Carme Moragues⁹, Sergi Ros⁵, Enrique Casado Burgos⁶, Vicente Torrente¹⁰, Elizabeth Garcia¹¹, Manel Pujol¹², Andrés Ponce¹³, Silvia Vidal⁴ and Juan José de Agustín¹⁴, ¹Rheumatology, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, Spain, ²Rheumatology, Hospital Moisès Broggi-Hospital General de L´Hospitalet. Consorci Sanitari Integral, Barcelona, Spain, ³Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, ⁴Institut de Recerca Sant Pau, Barcelona, Spain, ⁵Rheumatology, Hospital de Viladecans, Viladecans, Spain, ⁶Rheumatology, Parc Tauli Hospital Universitari, Sabadell, Spain, ⁷Rheumatology, Hospital General de Granollers, Granollers, Spain, ⁸Rheumatology Service, Hospital Clínic de Barcelona, Barcelona, Spain, ⁹Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, ¹⁰Hospital Moisès Broggi-Hospital General de L´Hospitalet. Consorci Sanitari Integral, L'Hospitalet de Llobregat, Spain, ¹¹Rheumatology, Hospital de Mollet, Mollet, Spain, ¹²Hospital Mútua de Terrassa, Terrassa, Spain, ¹³Rheumatology. Internal Medicine, Hospital General de Granollers, Granollers, Spain, ¹⁴Rheumatology, Hospital Vall d´Hebrón, Barcelona, Spain

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: IL-6, rheumatoid arthritis (RA) and tocilizumab

Session Information

Date: Monday, November 6, 2017

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy Poster II: Prognostic Factors, Imaging and Miscellaneous Reports

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling of IL-6/IL-6R complex, is an effective treatment in chronic inflammatory rheumatoid arthritis (RA). Although IL-6 contributes significantly to RA pathology, it is unknown how tocilizumab regulates the immune response of these patients.

Methods: Heparinized blood and clinical data from 47 RA patients were collected before treatment (t0) and after 12 months (t12m). Plasmatic cytokines were measured by ELISAs and phenotyping of circulating T CD4+ lymphocytes (memory, naïve, Tregs and Th subsets) was analyzed by flow cytometry.

Results:

Clinical and disease characteristics of the patients are shown in table 1. At t0 and at t12m, the concentrations of IL-6 and IL-10 and the concentrations of IL-17, VEGF and IL-22 correlated. After 12m with tocilizumab, the concentrations of sIL-6R and IL-10 significantly increased. Despite the decrease of CD4+ T lymphocytes, the percentages of Tregs and the Treg subset CD45RA+ significantly increased. No differences were observed in the percentages of Th1, Th2 and Th17 between t0 and t12m. However, the percentages of Th9 and Th9 CD45RO+ significantly decreased (Table 2). When patients were segregated according to EULAR response to tocilizumab (NR= no responders, R= responders), sIL6R (at t12m, NR=652±83 vs. R=1731±160 ng/ml, p=0.02) and monocytes/ul (at t12m, NR=840±40 vs. R=610±30, p=0.02) decreased and the ratio t12m/t0 of TregCD45RO+ increased (NR=0.49±0.15 vs. R=0.91±0.005, p=0.01) only in those patients with good or moderate response.

Conclusion: Despite the blocking of IL-6/IL-6R in all RA patients, changes in soluble mediators and T cell subsets were different between EULAR responders and non-responders to tocilizumab. Further information would be necessary to understand the immunological mechanisms operating in the different groups of patients.

Table 1. Baseline demographic and disease characteristics of the RA patients
Age; years (mean±SD)	53.8±11.1
Women; n (%)	40 (85.1)
Years of disease (mean±SD)	12.7±8.4
Positive Rheumatoid Factor; n (%)	31 (66%)
Positive ACPAs; n (%)	35 (74.5%)
Tocilizumab on monotherapy	17 (36.2%)
Used as first line biologic therapy; n (%)	14 (29.8%)
DAS28 (mean±SD)	5.65±1.15
CDAI (mean±SD)	28.2±13.3
ESR; mm/h (mean±SD)	46.5±30.8
CRP; mg/l (mean±SD)	24.9±30.8

Table 2. Immunological parameters at baseline and after 1 year of treatment
	t0			t12m
	mean		sem	mean		sem	(paired t-test)
IgG	1193.55	±	66.83	915.52	±	65.94	0.001
IgA	309.03	±	21.60	232.14	±	18.39	<0.001
IgM	156.09	±	14.00	128.30	±	15.86	0.195
Monocytes	0.67	±	0.07	0.66	±	0.08	0.445
Neutrophils	4.82	±	0.33	3.93	±	0.33	0.017
Lymphocytes	2.22	±	0.16	2.11	±	0.15	0.287
IL6pg/ml	670.52	±	129.89	849.74	±	183.31	0.066
sIL6R ng/ml	332.59	±	45.10	1592.92	±	158.32	<0.001
IL17 pg/ml	2044.40	±	945.86	1481.00	±	638.81	0.187
IL22 pg/ml	4960.60	±	1261.10	5461.28	±	1288.02	0.414
VEGF pg/ml	590.07	±	227.16	566.15	±	246.19	0.261
IL10 pg/ml	100.00	±	39.00	119.00	±	18.00	0.035
CD4 (% lymphocytes)	46.99	±	1.58	44.92	±	1.22	0.041
Treg (% CD4+ T cells)	6.66	±	0.28	7.38	±	0.27	0.026
Th1 (% CD4+ T cells)	7.79	±	1.05	6.72	±	0.51	0.420
Th17 (% CD4+ T cells)	10.78	±	1.85	6.81	±	0.48	0.130
Th2 (% CD4+ T cells)	8.53	±	1.35	6.41	±	0.32	0.220
Th9 (% CD4+ T cells)	13.75	±	1.85	6.78	±	0.64	0.002

Disclosure: C. Diaz-Torné, None; P. Estrada, None; P. Moya, None; M. A. Ortiz, None; D. de la Fuente, None; M. Moreno, None; N. Busquets, None; J. Ramírez, Gebro, 2; C. Moragues, None; S. Ros, None; E. Casado Burgos, None; V. Torrente, None; E. Garcia, None; M. Pujol, None; A. Ponce, None; S. Vidal, None; J. J. de Agustín, None.

To cite this abstract in AMA style:

Diaz-Torné C, Estrada P, Moya P, Ortiz MA, de la Fuente D, Moreno M, Busquets N, Ramírez J, Moragues C, Ros S, Casado Burgos E, Torrente V, Garcia E, Pujol M, Ponce A, Vidal S, de Agustín JJ. Changes in the Immune Response of RA Patients Induced By 1 Year of Tocilizumab [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/changes-in-the-immune-response-of-ra-patients-induced-by-1-year-of-tocilizumab/. Accessed .

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